Lou'sCommunication

Lou'sCommunication - Published on Web 09/01/2006 A...

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A Pro-Chelator Triggered by Hydrogen Peroxide Inhibits Iron-Promoted Hydroxyl Radical Formation Louise K. Charkoudian, David M. Pham, and Katherine J. Franz* Department of Chemistry, Duke Uni V ersity, P.O. Box 90346, Durham, North Carolina 27708 Received July 6, 2006; E-mail: [email protected] Neurodegenerative diseases such as Parkinson’s and Alzheimer’s diseases show signs of increased oxidative stress that result when reactive oxygen species (ROS) overwhelm a cell’s inherent anti- oxidant mechanisms. 1 - 4 Markers of oxidative stress include lipid peroxidation, DNA base hydroxylation, and protein modification, all of which are attributed to the highly reactive hydroxyl radical, OH . While many potential antioxidant therapies use radical scavengers in attempts to mitigate cellular damage, such strategies do not inhibit formation of these harmful radicals. A principal mechanism for the formation of OH is via iron- promoted reactions like the Fenton reaction (eq 1), 5 which becomes catalytic if cellular reductants can reduce Fe 3 + to Fe 2 + . In order for iron to promote Fenton chemistry, it must be in a coordination environment that favors redox cycling and allows reactants access to the inner sphere of the metal center. 6 These requirements imply that loosely bound iron that is not properly regulated by the cell’s normal metal trafficking and storage mechanisms contributes to oxidative stress. 1,2,4 Chelating agents that can selectively sequester this pool of iron could potentially inhibit iron-promoted oxidative stress by inactivating the source itself. Although several chelators that were developed to treat iron overload diseases have some desirable properties for treating neurodegenerative diseases, 7 - 10 they also have troubling draw- backs. 11 Their high affinity for iron means that they compete with iron-binding proteins, thereby altering healthy iron distribution and inhibiting essential iron-containing enzymes. Furthermore, their intrinsic affinity for other metal ions disrupts the availability of key elements like zinc. To overcome these limitations, we are developing a class of pro- chelators that have little to no affinity for metal ions until a protective mask is selectively removed by ROS, as demonstrated in Scheme 1 for H 2 O 2 . In the absence of oxidative stress, these masked molecules are poor ligands that cannot alter healthy metal ion distribution, a common toxicity issue associated with currently available chelation therapies. Disease conditions that elevate oxidative stress, however, activate the chelator to reveal a high-
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This note was uploaded on 10/19/2011 for the course CHEM 197 taught by Professor Bonk during the Summer '11 term at Duke.

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Lou'sCommunication - Published on Web 09/01/2006 A...

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